Research letter
European Journal of Preventive
Primum non nocere: An updated
meta-analysis on aspirin use in primary
prevention of cardiovascular disease
in patients with diabetes
Federico Fortuni1, Gabriele Crimi2, Valeria Gritti2,
Alessandro Mandurino Mirizzi1, Sergio Leonardi1
and Gaetano M De Ferrari1
Individuals with diabetes have a two- to four-fold
increased risk of vascular events.1 A pivotal role in
this setting is played by an exaggerated platelet activa-
tion. This has led to increasing interest over recent dec-
ades in developing interventions aimed at reducing
cardiovascular risk in this population. Although the
effectiveness of aspirin in secondary prevention of
cardiovascular disease (CVD) in diabetes is established,
its use in primary prevention is still controversial2 and
current European Society of Cardiology guidelines on
CVD prevention do not provide a clear recommenda-
tion.3 A number of randomized trials have reported on
the role of aspirin in primary prevention of CVD in
people with diabetes, but the majority of these studies
were poorly powered with regard to the number of
people with diabetes and reported results from
subgroups.4 The recently published ASCEND trial pro-
vided new evidences specifically assessing this issue in a
large population of diabetic patients.5
We performed an updated study-level meta-analysis
to evaluate the efficacy and safety of aspirin in primary
prevention of CVD in diabetic patients. Electronic
databases were searched for clinical trials that rando-
mized diabetic patients without previous cardiovascular
events to aspirin or placebo. The process was per-
formed according to the PRISMA statement.6 Two
authors extracted data on patient characteristics and
outcomes. Efficacy outcomes were major adverse cardi-
ovascular event (MACE), myocardial infarction (MI),
stroke, and cardiovascular and all-cause mortality.
Safety endpoints were major bleedings and malignan-
cies. Net adverse clinical events (NACEs) were com-
puted as the unweighted sum of haemorrhagic stroke,
major extracranial bleeding, ischaemic stroke and MI
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and as weighted sum of fatal equivalent of the above
events using weights and methods previously reported.7
Random-effects risk ratios (RRs) were estimated using
a Mantel–Haenszel method with a person-year
approach. Heterogeneity was calculated using the I2
test and publication bias was visually assessed with
funnel plots. Univariate meta-regression for unadjusted
log-RR was performed to explore the potential mod-
erator effect of mean age, aspirin dose, smoking status,
hypertension, gender, type of diabetes, concomitant
statin therapy and compliance to study treatment on
MACE. Statistical analyses were conducted using
Review Manager version 5.3 and OpenMeta-Analyst.
Five trials met our inclusion criteria and were
included in the analyses (N ¼ 24,037; mean follow-up
5.43  1.56 years; Table 1). Aspirin reduced the risk
of MACE compared with placebo (1.5% vs. 1.7%
person-year; RR: 0.90; 95% confidence interval (CI):
0.83–0.97; p ¼ 0.004; number needed to treat (NNT)
over the mean follow-up ¼ 88). As shown in Figure 1
the risk of MI, stroke, and cardiovascular and all-cause
mortality did not differ between the two groups. Aspirin
significantly increased the risk of major bleedings com-
pared with placebo (0.53% vs. 0.43% person-year; RR:
1.24; 95% CI: 1.06–1.45; p ¼ 0.03; number needed to
1
Coronary Care Unit and Laboratory of Clinical and Experimental
Cardiology - Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
2
Division of Cardiology - Fondazione IRCCS Policlinico San Matteo, Pavia,
Italy
Corresponding author:
Gabriele Crimi, Division of Cardiology, Fondazione IRCCS Policlinico San
Matteo, Piazzale Golgi 1, 27100 Pavia, Italy.
Email: gabrielecrimi@gmail.com
2 European Journal of Preventive Cardiology 0(00)

Table 1. Study characteristics.

Patients Mean age Mean FU Male BMI Hypertension Statin use Aspirin Compliance
Study n (years) (years) (%) (kg/m2) (%) (%) dose (mg) (%)

ASCEND 15,480 63.3 7.4 62.6 30.7 61.6 75.3 100 70

ETDRS 3711 NA 5 56 NA 74.1 0 650 72.2
JPAD 2539 65 4.37 55 24 58 26 100 or 81 90
POPADAD 1276 60.3 6.7 44.1 29.25 NA NA 100 50
PPP 1031 64.2 3.7 48.2 29 60.5 12.7 100 71.8
ASCEND: A Study of Cardiovascular Events iN Diabetes; BMI: body mass index; ETDRS: Early Treatment Diabetic Retinopathy Study; FU: follow-up;
JAPD: Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; NA: not available; POPADAD: Prevention Of Progression of Arterial
Disease And Diabetes; PPP: Primary Prevention Project

Endpoints - n. of studies considered Estimate (95% CI) Events/ patient -years aspirin Events/patient -Years placebo

MACE - 5 0.898 (0.831, 0.970) 1201/78266 1338/78300

MI - 5 0.923 (0.822, 1.038) 539/78266 584/78300
Stroke - 5 0.923 (0.801, 1.063) 368/78266 399/78300
CV mortality - 5 0.909 (0.805, 1.026) 495/78266 545/78300
All-cause mortality - 5 0.943 (0.873, 1.018) 1241/78266 1317/78300
Major bleeding - 3 1.239 (1.061, 1.447) 354/67066 286/67131
Weighted NACE - 3 1.039 (0.946, 1.142) 866/67066 834/67131
Unweighted NACE - 3 1.032 (0.939, 1.133) 872/67066 846/67131
Cancer - 3 0.976 (0.849, 1.066) 960/63471 983/63445

0.8 0.97
1.45
Relative risk (log scale)

Figure 1. Efficacy and safety outcomes: aspirin versus placebo in primary prevention.
CI: confidence interval; CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction; NACE: net adverse
clinical event

harm (NNH) over the mean follow-up ¼ 141). The risk
of malignancies and of NACE did not differ between the
two groups. No publication bias was detected, both for
efficacy and safety outcomes. These results were con-
firmed also after excluding the Early Treatment
Diabetic Retinopathy Study, which included 26% of
patients with a previous cardiovascular event.8 The uni-
variate meta-regression did not show any moderator
effect on MACE of the variables considered.
We must acknowledge some limitations. The defini-
tion of major bleedings was not consistent across the
trials; however, we carefully revised and included
specific major haemorrhagic events in the NACE
computation. The absence of any moderator effect in
the meta-regression may be due to a type two error
related to the limited number of studies included in
the analyses.
Aspirin significantly reduced by 10% the risk of
MACE compared with placebo, whereas the reduction
in the risk of individual hard efficacy endpoints did not
reach statistical significance. This modest benefit was
accompanied by a 24% increased risk of major bleed-
ings and no net clinical benefit was detected. Although
the NNT to reduce a MACE in diabetic patients is
inferior to the NNH to induce a major bleeding, this
updated meta-analysis suggests that aspirin does not
provide a clear and significant net clinical benefit
when indistinctly used in primary prevention of CVD
in patients with diabetes.
Author contribution
GC is responsible for the study rationale, manuscript
drafting and final review. VG and AMM performed the lit-
erature search. FF and VG assessed the selected articles and
collected the data of interest. FF drafted the manuscript and
performed the statistical analyses. All authors were involved
in conception and the design of the study and interpretation
of the data, revised the manuscript critically for important
intellectual content and finally approved the manuscript
submitted.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Fortuni et al.
References
1. Emerging Risk Factors Collaboration. Diabetes mellitus,
fasting blood glucose concentration, and risk of vascular
disease: A collaborative meta-analysis of 102 prospective
studies. Lancet 2010; 375: 2215–2222.
2. Ridker PM. Should aspirin be used for primary prevention
in the post-statin era? N Engl J Med 2018; 379: 1572–1574.
3. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European
Guidelines on cardiovascular disease prevention in clinical
practice: The Sixth Joint Task Force of the European
Society of Cardiology and Other Societies on
Cardiovascular Disease Prevention in Clinical Practice.
Developed with the special contribution of the European
Association for Cardiovascular Prevention & Med 2015; 128: 1007–14.e2.
Rehabilitation (EACPR). Eur Heart J 2016; 37:
2315–2381.
4. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for
primary prevention of cardiovascular events in people with
3
diabetes: Meta-analysis of randomised controlled trials.
BMJ 2009; 339: b4531.
5. The ASCEND Study Collaborative Group. Effects of
aspirin for primary prevention in persons with diabetes
mellitus. N Engl J Med 2018; 379: 1529–1539.
6. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA
statement for reporting systematic reviews and meta-ana-
lysis of studies that evaluate health care interventions:
Explanation and elaboration. Ann Intern Med 2009; 151:
w1–w30.
7. Renda G, di Nicola M and De Caterina R. Net clinical
benefit of non-vitamin K Antagonist oral anticoagulants
versus warfarin in phase III atrial fibrillation trials. Am J
8. ETDRS Investigators. Aspirin effects on mortality and
morbidity in patients with diabetes mellitus. Early
Treatment Diabetic Retinopathy Study report 14. JAMA
1992; 268: 1292–1300.